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The Wnt signaling pathway is crucial for numerous regulatory processes in the developing and mature organism. Deregulation of the Wnt pathway can introduce malformation, loss of form, cancer, and other malfunctions. Understanding this pathway and its direct effects on specific developmental processes can lead to new methods to reverse or treat Wnt related issues. As we continue to learn about the Wnt pathway, we come closer to understanding various mechanisms of animal development.
In this study in particular, the researchers investigated a Wnt inhibitor from the Dickkopf family, Dickkopf 1 (DKK1). DKK1 inhibits the Wnt pathway by binding LRP5/6, a co-receptor of Frizzled. In the chicks exposed to DKK1, the levels of β-catenin, transcription factor 4, c-myc, and cyclin D1 all decreased. The reduction of these allows us to see the impacts of DKK1 to typical products of an activated Wnt pathway. For example, cyclin D1 is an oncogene involved in enhancing cell division that when upregulated can lead to cancers. This gene is turned on by Wnt activated transcription factors. Therefore, a decrease in cyclin D1, and others like, indicates inhibition of the pathway. Injection of high and low dosages of DKK1 into chick eggs led to reduced density and amount of follicles and thus reduced feathers on the day of hatching. Increased dosages also increased the effects of DKK1 because Wnt was likely inhibited at higher levels.
This study highlights the importance of an active Wnt signaling pathway for proper feather development. Wnt is active in normal morphogenesis for follicle development and feather growth in chicks. The research demonstrates yet another function of the pathway and how its deregulation results in disadvantageous phenotypes. A highly regulated Wnt pathway is crucial to proper function and form in a myriad of organisms.
Links related to the paper:
Development, Regeneration, and Evolution of Feathers
Structural Basis of Wnt Signaling Inhibition by Dickkopf Binding to LRP5/6
A Series of Normal Stages in the Development of the Chick Embryo
Function and Biological Roles of Dickkopf Family of Wnt Modulators
The Wnt Signaling Pathway is important to the regulation of crucial aspects of cell fate determination, cell migration, cell polarity, neural patterning and organogenesis during embryonic development some of which we have discussed this semester. An important issue that arises from the suppression of the Wnt signaling pathway is the hypoplasia of the zona glomerulosa and (importantly) as well as the zona reticularis. Hyploplasia means that there is underdevelopment or incomplete development of a tissue or an organ, in this case the zona glomerulosa and zona reticularis. Zona glomerulosa (outermost layer) and zona reticularis (inner most layer) are part of the functional and histological zones of the adrenal cortex. Said zones are important for the zone of proliferation which takes charge in the production of bone tissue and is a region for active cell replication.
A way in which the Wnt signaling pathway can be suppressed is due to the effects of exposure to an endocrine disruptor during prenatal and postnatal development, specifically, dichlorodiphenyltrichloroethane (DTT). DTT was first used as a pesticide and was efficient until the discovery of its serious negative effects. DTT bioaccumulates as it moves through the food chain, which means that like plastic, it is never fully degraded and continues to accumulate throughout organisms that ingest it. This began to be a concern to the long-term harmful effects especially after discovery of carcinogenic effects in which negative neurobehavioral functions were associated with it as well. Endocrine disruptors, such as DTT, that have a low molecular weight and high lipophilicity have the ability to overcome the blood-tissue barriers (including the placental barrier) and interrupt the development of organs and systems of the embryo, particularly the endocrine system.
The goal of this research was to investigate the role of the canonical Wnt/β-catenin signaling pathway in the morphogenesis (biological process that causes a cell, tissue or organism to develop its shape) and regeneration (natural process of replacing or restoring damaged or missing cells, tissues, organs, and even entire body parts) of the adrenal cortex of immature rats exposed to the endocrine disruptor DDT in prenatal and postnatal ontogeny. The authors investigated and found that changes in the activation of the canonical Wnt/β-catenin signaling pathway are directly involved in the disruption of postnatal morphogenesis of the adrenal cortex caused by the endocrine disruptor DDT as they compared prenatal and postnatal exposure to low doses of DDT.
Links related to the paper:
Dichlorodiphenyltrichloroethane (DDT): Ubiquity, Persistence, and Risks
Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement
Dichlorodiphenyltrichloroethane (DDT), DDT metabolites and pregnancy outcomes
Adrenal cortex tissue homeostasis and zonation: A WNT perspective
In the Hedgehog signaling pathway, where there is the absence of Hedgehog ligand, Gli is phosphorylated by protein kinase, and leads to development of Gli repressor. The Gli repressor represses the expression of target genes. When the Hedgehog ligand is binded the smoothened protein is phosphorylated by protein kinase A and casein kinase 1. The inhibitory effect of Sufu is removed and Gli activator induces transcription of target genes. Here the researchers describe how when abnormally activated, the hedgehog signaling pathway is involved in the occurrence and development of tumors. This led to them reasoning that inhibition of the pathway could potentially block cervical cancer.
In organisms the total number of cells is a balance between the cell-generating effects of mitosis and cell death, which is induced through apoptosis. A disruption of this balance can lead to the development of cancer. Resveratrol, a non-flavonoid polyphenol compound, was found to have inhibitory effects on the progression of tumors and promoted apoptosis. The study focused on the effects of resveratrol on apoptosis, migration and/or invasion of cervical cancer cells and understanding a potential mechanism of resveratrol against cervical cancer.
It was found that resveratrol did in fact induce apoptosis, and suppress migration/invasion of cervical cancer cells through the inhibition of the hedgehog signaling pathway in HeLa cells.
Links related to the paper:
Radioresistance to Cervical Cancer
Cervical cancer-originated HeLa cells
The Wnt signaling pathway is necessary for the activation of genes and the expression of epithelial-mesenchymal transition (EMT). EMT is the process in which the epithelial cells transition into mesenchymal cells and the epithelial markers are downregulated while the mesenchymal markers are upregulated. The dysregulation of the Wnt pathway can cause the development of cancers such as lung and colon cancer. It is necessary to understand how the Wnt signaling pathway and EMT can regulate the expression of epithelial ovarian cancer (EOC).
The purpose of this study is to find out how salinomycin affects epithelial ovarian cancer (EOC).These findings are important because EOC is mostly detected when the only option is surgery and cytotoxic chemotherapy, so it would be helpful if salinomycin can target those cells. The results showed that salinomycin downregulates proteins from the Wnt pathway, represses the translocation of B-catenin, and reverses the canonical Wnt pathway induced by GSK-3B inhibitor. Also, salinomycin causes the opposite reaction of EMT because it increases epithelial markers and decreases the expression of mesenchymal markers.
Based on the research, salinomycin inhibits the migration, proliferation, and invasion in EOC cells. This drug creates an inhibitory effect not only in EOC cells, but also in the Wnt pathway and changes the expression of EMT markers. This is a very important finding for future treatment of epithelial ovarian cancer.
Links related to the paper:
The epigenetics of epithelial-mesenchymal plasticity in cancer
This study aimed to further understand both the function as well significance of the coatomer protein complex subunit B2 (COPB2) in gastric cancer, which was the first study to be published on the effects of COPB2 on gastric cancer. Because of this, there was a sense of urgency to investigate the silencing of COPB2 effects on cancerous gastric cells to further understand its role in gastric cancer tumorigenesis and possibly to uncover a potential biomarker and target gene for therapy to counteract the effects. It has previously been reported that COPB2 may be a target gene in prostate cancer cell limes, in addition, RNA interference-mediated knockout of COPB2 has been documented to have significantly inhibit growth of pulmonary cancer cells and colony formation of colon cancer cell lines. These findings are indicative that COPB2 could possibly be a target for cancer gene therapy.
In order to conduct this study and to measure COPB2 expression in gastric cancer cell limes, reverse transcription-quantitative polymerase chain reaction analysis was used and lentivirus-short hairpin RNA (shRNA) COPB2 was generated. This allowed for the infection of gastric cancer cells which further helped to analyze the effects of COPB2 on cancerous phenotypic cells. The effects that shRNA-mediated COPB2 knockout on cell proliferation yielded were detected using both colony formation assays, in addition, the effects of COPB2 on apoptosis were analyzed via flow cytometry. The molecular mechanisms of the underlying effects of COPB2 knockout was explored using a receptor tyrosine kinase (RTK) signaling antibody array.
The results revealed COPB2 mRNA was abundant and over-expressed in gastric cancer cell lines. Similarly, knockout of COPB2 inhibited cell growth as well as colony formation ability significantly and also led to an increase of cell apoptosis in vitro. The findings from the antibody array assay showed reduced phosphorylation levels in over twenty target RTKs. It was concluded from these findings that COPB2 was expressed highly in gastric cancer cell lines and knockout of COPB2 suppressed colony formation in addition to promoting cell apoptosis by inhibiting the RTK signaling with its coupled downstream signaling cascade molecules. This study concluded COPB2 may be an effective target for gene silencing in gastric cancer.
Links related to the paper:
Signaling pathways and therapeutic interventions in gastric cancer
Targeting RTK signaling pathways in cancer
This paper focuses on the teratogenic effects of Glyphosate based Herbicide (GBH), also known as 'Roundup' on the development of chick embryos. The purpose of this experiment is to determine if this widely used agricultural herbicide is detrimental to human health. There have been many studies conducted on GMOs like this herbicide that indicate possible adverse side effects on environment and human health. There are such reports of neural defects and craniofacial malformations. Glyphosate has contaminated land, water, air, and the food chain so it is definitely leaking into human consumption.
Originally, glyphosate was thought to be safer than other herbicides posing less of a health risk due to the initial thought of low toxicity, however it was found that it may induce apoptosis and necrosis in the human umbilical cord.
In this study, chick embryos were used to determine the toxicity of glyphosate on development to determine how this could be impacting human development. The chicks were injected with different amounts of 'Roundup' herbicide, diluted with saline and left to grow for several days. The survival and mortality rates were recorded on day 3, day 6, and day 10. All groups showed more or less malformations and growth retardation. Measurements and analysis of body parameters were also conducted, and all experimental groups measured significantly less than the control group. Results indicated that glyphosate-based herbicide (Roundup) caused lethality in every concentration from day 3, 6, and 10. These finding may also indicate the same effects for miscarriages in humans.
Many researchers question why this herbicide is still being used despite these findings, but future research will need to be conducted to determine the teratogenic effects of GBH in different methods of ingestion to determine its adverse effects.
Links related to the paper:
Glyphosate (Roundup): Understanding Risks to Human Health
Glyphosate toxicity for animals
The p53 tumor suppressor gene is the 'guardian of the genome' preventing tumorigenesis as it regulates gene expression through the cell cycle and blocking entry into the S phase if the DNA is damaged. Long coding RNA (RMRP) is the RNA component of mitochondrial RNA-processing endoribonuclease and plays an oncogenic role as it inhibits p53 through MDM2 protein which promotes unregulated cell growth. MDM2 is a E3 ubiquitin ligase used by RMRP to regulate p53 since p53 does not get inhibited directly by RMRP.
In this study the researchers identified RMRP as an inhibitor of p53 and when it is overexpressed it is associated with a negative prediction in colorectal cancer in both vitro and in vivo. The ectopic RMRP suppresses the activity of p53 by promoting MDM2 protein that ubiquitinates p53. Ubiquitination is a process in which ubiquitin molecules attach to a protein substrate to promote protein degradation. Researchers tested this by generating a RMRP-knockout HCT116 cell line to analyze the role of RMRP in colorectal cancer. The HCT116 cell line is human colon cancer from a male to be used as a model. A mutation occurs in this proto-oncogene to become an oncogene. Depletion of RMRP was found to activate the p53 pathway and instead allowed it to function properly.
This study highlighted the importance of tumor suppressor p53 specifically in regards to colorectal cancer and found that highly expressed RMRP is associated with unfavorable cancer prognosis, RMRP hinders p53 activity by enhancing the function of MDM2 function, RMRP promotes cancer cell growth through inactivation of p53 as seen in vivo as well.
Links related to the paper:
The role of ubiquitination and deubiquitination in cancer metabolism
Role of p53 in Cell Death and Human Cancers
The emerging role of long noncoding RNA RMRP in cancer development and targeted therapy
Targeting MDM2-p53 Interaction for Cancer Therapy